ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.865A>G (p.Ile289Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(4); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.865A>G (p.Ile289Val)
Variation ID: 217400 Accession: VCV000217400.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101398504 (GRCh38) [ NCBI UCSC ] X: 100653492 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 11, 2016 May 1, 2024 Dec 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.865A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Ile289Val missense NM_001199973.2:c.300+3047T>C intron variant NM_001199974.2:c.177+6682T>C intron variant NR_164783.1:n.944A>G non-coding transcript variant NC_000023.11:g.101398504T>C NC_000023.10:g.100653492T>C NG_007119.1:g.14460A>G LRG_672:g.14460A>G LRG_672t1:c.865A>G P06280:p.Ile289Val - Protein change
- I289V
- Other names
- NM_000169.2(GLA):c.865A>G(p.Ile289Val)
- Canonical SPDI
- NC_000023.11:101398503:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00026 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD) 0.00009
Exome Aggregation Consortium (ExAC) 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00016
1000 Genomes Project 0.00026
1000 Genomes Project 30x 0.00125
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6 | 1237 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1267 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Dec 29, 2023 | RCV000209743.20 | |
drug response (1) |
no assertion criteria provided
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Jan 1, 2014 | RCV000209181.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 24, 2017 | RCV000236089.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 25, 2019 | RCV001507540.10 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 29, 2020 | RCV002444817.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jan 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539243.1
First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in one patient with Fabry disease. It is present in ExAC with a Max MAF of 0.11% in Latino chrs (with 2 hemizygotes). It's been seen in 1 female with symptoms of Fabry disease. It is classified in ClinVar with 1 star as VUS by GeneDx and Albrecht-Kossel-Institute,Medical University Rostock. (less)
Method: Genome/Exome Filtration
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Benign
(May 31, 2018)
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criteria provided, single submitter
Method: curation
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Fabry disease
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000803618.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
This variant is interpreted as a Benign, for Fabry disease, in X-linked Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is … (more)
This variant is interpreted as a Benign, for Fabry disease, in X-linked Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:26415523). (less)
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Likely benign
(Nov 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000294058.11
First in ClinVar: Jul 24, 2016 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 26415523, 27916943)
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Likely benign
(Dec 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000622194.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
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Uncertain significance
(Sep 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713145.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Likely benign
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002054803.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422797.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022
Comment:
X-linked inheritance (primarily recessive with milder female expression)
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Comment:
The p.Ile289Val variant in GLA has been reported in 4 female individuals with unknown Fabry disease phenotype (PMID: 26415523), and has been identified in 0.096% … (more)
The p.Ile289Val variant in GLA has been reported in 4 female individuals with unknown Fabry disease phenotype (PMID: 26415523), and has been identified in 0.096% (27/28054) of Latino chromosomes, including 9 hemizygotes, and 0.032% (6/19042) of African chromosomes, including 2 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140329381). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by GeneDx, the Laboratory for Molecular Medicine, and the Albrecht-Kossel-Institute, and as likely benign and benign by Invitae and the Swiss Institute of Bioinformatics, respectively (ID: 217400). In vitro functional studies provide some evidence that the p.Ile289Val variant may not impact protein function (PMID: 26415523). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional pathogenic variant, causing a different amino acid change at the same position, p.Ile289Phe, has been reported in association with Fabry disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 21598360, 10666480/Variation ID: 92568). In summary, while the clinical significance of the p.Ile289Val variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, PM5_supporting, BS3_supporting (Richards 2015). (less)
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Uncertain significance
(Jan 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001735639.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces isoleucine with valine at codon 289 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces isoleucine with valine at codon 289 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373).One study has shown this variant has little impact on GLA enzyme activity (PMID: 26415523). The same study has also shown normal lysoglobotriaosylceramide levels in a few female individuals who underwent biochemical analysis or genetic testing for Fabry Disease (PMID: 26415523). This variant has been identified in 33/205394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Mar 29, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002683329.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Jan 01, 2014)
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no assertion criteria provided
Method: research
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Fabry's disease
Affected status: unknown
Allele origin:
inherited
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Albrecht-Kossel-Institute, Medical University Rostock
Accession: SCV000246077.1
First in ClinVar: Mar 11, 2016 Last updated: Mar 11, 2016 |
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drug response
(Jan 01, 2014)
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no assertion criteria provided
Method: research
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deoxygalactonojirimycin response
Drug used for
Fabry disease
Affected status: unknown
Allele origin:
inherited
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Albrecht-Kossel-Institute, Medical University Rostock
Accession: SCV000246078.1
First in ClinVar: Mar 11, 2016 Last updated: Mar 11, 2016 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease. | Lukas J | Human mutation | 2016 | PMID: 26415523 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/53d16b3e-ab4a-478f-b0dd-afe7821e631e | - | - | - | - |
Text-mined citations for rs140329381 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.